Project Summary The applicant's career goal is to develop a multidisciplinary research program focused on defining how inflammation contributes to the development of metabolic disease. Emerging data from the past decade has revealed that obesity-induced metabolic inflammation is a key driving force in the pathogenesis of Type 2 diabetes mellitus (T2DM). In the adipose tissue, liver, and muscle, it is well recognized that obesity leads to progressive infiltration of activated pro-inflammatory macrophages and other leukocytes that act in concert to induce insulin resistance and metabolic dysfunction. At present, relatively little is known about whether and how islet-associated macrophages contribute to islet inflammation, glucose intolerance, and beta cell dysfunction in T2DM. Furthermore, the phenotype, function, and regulation of islet-associated macrophages during the progression of metabolic inflammation and T2DM have yet to be fully defined, leaving critical gaps in our understanding of the pathogenesis of this serious metabolic disease. The central hypothesis of this application is that obesity-induced metabolic stress causes the accumulation of pro-inflammatory macrophages within the islet that exacerbate beta cell dysfunction in T2DM. To test this hypothesis and to begin to uncover the role of islet-associated macrophages in the progression of T2DM, three Specific Aims are proposed. Aim 1 will determine the immunophenotype and inflammatory profile of islet-associated macrophages during the progression of glucose intolerance and T2DM in mouse models. Aim 2 will define the interplay between beta cell endoplasmic reticulum (ER) stress and recruitment and activation of islet-associated macrophages. Aim 3 will investigate the effects of pro-inflammatory macrophages on beta cell secretory function in obesity and T2DM. The diverse experimental approaches outlined in the research plan will allow the applicant to broaden his diabetes expertise by developing new proficiencies and complementary skill sets in the assessment of beta cell function in mouse models, isolated islets, and commonly used beta cell lines. The applicant will benefit from training in the Basic Diabetes Research Group within the Herman B Wells Center for Pediatric Research at the Indiana University School of Medicine, which houses five laboratories that are committed to understanding the molecular mechanisms that lead to the development of all forms of diabetes mellitus. This new training in islet biology will complement the applicant's previous training in physiology, metabolism, and obesity-induced inflammation. A diverse team of established investigators will oversee the applicant's career development during the award period by contributing intellectually to his research training, providing mentorship, and offering career advice.